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Zheng, D; Arima, H; Sato, S; Gasparrini, A; Heeley, E; Delcourt,
C; Lo, S; Huang, Y; Wang, J; Stapf, C; Robinson, T; Lavados, P;
Chalmers, J; Anderson, CS; INTERACT2 investigators (2016) Low
Ambient Temperature and Intracerebral Hemorrhage: The INTERACT2 Study. PLoS One, 11 (2). e0149040. ISSN 1932-6203 DOI:
10.1371/journal.pone.0149040
Downloaded from: http://researchonline.lshtm.ac.uk/2528905/
DOI: 10.1371/journal.pone.0149040
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RESEARCH ARTICLE
Low Ambient Temperature and Intracerebral
Hemorrhage: The INTERACT2 Study
Danni Zheng1,2, Hisatomi Arima1,2,3, Shoichiro Sato1, Antonio Gasparrini4, Emma Heeley2,
Candice Delcourt1,2,5, Serigne Lo2, Yining Huang6, Jiguang Wang7, Christian Stapf8,9,
Thompson Robinson10, Pablo Lavados11, John Chalmers1, Craig S. Anderson1,2,5*,
INTERACT2 investigators¶
OPEN ACCESS
Citation: Zheng D, Arima H, Sato S, Gasparrini A,
Heeley E, Delcourt C, et al. (2016) Low Ambient
Temperature and Intracerebral Hemorrhage: The
INTERACT2 Study. PLoS ONE 11(2): e0149040.
doi:10.1371/journal.pone.0149040
Editor: Xiaoying Wang, Massachusetts General
Hospital, UNITED STATES
Received: December 1, 2015
Accepted: January 26, 2016
Published: February 9, 2016
Copyright: © 2016 Zheng et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: An anonymized
version of the dataset used for the analysis in this
article will be made available to researchers upon
request through The George Institute for Global
Health research office. Requests for the dataset can
be made by contacting Mr Peter Dolnik, Director of
Research Services, The George Institute for Global
Health, GPO Box 5389, Sydney NSW 2001 Australia.
T: +61 2 9657 0369 E: [email protected]
Funding: The second Intensive Blood Pressure
Reduction in Acute Cerebral Hemorrhage Trial study
was supported by Program (571281) and Project
(512402 and 1004170) grants from the National
1 Division of Neurology and Mental health, The George Institute for Global Health, Sydney, New South
Wales, Australia, 2 Sydney Medical School, the University of Sydney, Sydney, New South Wales, Australia,
3 Centre for Epidemiologic Research in Asia, Shiga University of Medical Sciences, Shiga University, Shiga,
Japan, 4 Department of Social and Environmental Health Research, London School of Hygiene & Tropical
Medicine, London, United Kingdom, 5 Royal Prince Alfred Hospital, Camperdown, New South Wales,
Australia, 6 Department of Neurology, Peking University First Hospital, Beijing, China, 7 Centre for
Epidemiological Studies and Clinical Trials, The Shanghai Institute of Hypertension, Ruijin Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai, China, 8 Department of Neurology, APHP–
Hôpital Lariboisière, DHU NeuroVasc Paris–Sorbonne, Université Paris Diderot–Sorbonne Paris Cité, Paris,
France, 9 Department of Neuroscience, CRCHUM, University of Montreal, Montreal, Quebec, Canada,
10 Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in Cardiovascular Disease,
University of Leicester, Leicester, United Kingdom, 11 Vascular Neurology Program, Neurology Services,
Department of Internal Medicine, Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile
¶ A full list of INTERACT2 investigators is provided in the Acknowledgments.
* [email protected]
Abstract
Background
Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude
of risk is unknown. We aimed to quantify the association of ambient temperature with the
risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial
(INTERACT2) participants on an hourly timescale.
Methods
INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of
patients with spontaneous ICH (<6h of onset) and elevated systolic blood pressure (SBP,
150–220 mmHg) assigned to intensive (target SBP <140 mmHg) or guideline-recommended
(SBP <180 mmHg) BP treatment. We linked individual level hourly temperature to baseline
data of 1997 participants, and performed case-crossover analyses using a distributed lag
non-linear model with 24h lag period to assess the association of ambient temperature and
risk of ICH. Results were presented as overall cumulative odds ratios (ORs) and 95% CI.
Results
Low ambient temperature (10°C) was associated with increased risks of ICH: overall
cumulative OR was 1.37 (0.99–1.91) for 10°C, 1.92 (1.31–2.81) for 0°C, 3.13 (1.89–5.19)
for -10°C, and 5.76 (2.30–14.42) for -20°C, as compared with a reference temperature of
PLOS ONE | DOI:10.1371/journal.pone.0149040 February 9, 2016
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Ambient Temperature and ICH Onset
Health and Medical Research Council (NHMRC) of
Australia (URL: https://www.nhmrc.gov.au). AG was
supported by Medical Research Council-UK (Grant
ID: MR/M022625/1) (URL:https://www.mrc.ac.uk/).
The funders had no role in the study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
20°C.There was no clear relation of low temperature beyond three hours after exposure.
Results were consistent in sensitivity analyses.
Competing Interests: The authors have declared
that no competing interests exist.
Trial Registration
Conclusions
Exposure to low ambient temperature within several hours increases the risk of ICH.
ClinicalTrials.gov NCT00716079
Introduction
Acute stroke due to spontaneous (non-traumatic) intracerebral hemorrhage (ICH) is a major
global health issue which causes death and permanent disability in several million people
worldwide each year [1]. While marked seasonal and temporal patterns to the occurrence of
ICH are recognised, with peak incidence in the winter and an association with cold temperature [2–5], this information is primarily derived from daily meteorological data without consideration of ambient temperature close to the time of onset of ICH. Moreover, the time lag
method, which has shown an association of ambient temperature with acute myocardial infarction [6,7], has not been used in the study of ICH where influences on fluctuations in blood
pressure (BP) appear especially important [8]. Thus, the association of ambient temperature
with ICH onset has not been well quantified on an hourly time-scale. Such information could
help our understanding of the determinants of ICH in high risk populations that have marked
seasonal and geographical trends in rates [9], and guide public health strategies to optimize
preventative strategies in winter.
The primary aim of this study was to quantify the transient increase in risk of ICH associated with declining ambient temperature at an hourly resolution. Secondary aims were to
determine the time sequence of low temperature triggering effects on ICH occurrence and
whether there is any variation in risks across several pre-defined patient characteristics.
Materials and Methods
Ethics Statement
The INTERACT 2 study protocol was approved by the ethics committees for each centers and
written informed consent was obtained from all patients or relevant surrogates. A full list of
centers that participated in the trial is shown in Acknowledgments. Patient records/information was anonymized and de-identified prior to analysis.
Study Design
We conducted post-hoc analysis using the baseline patient data from the second (main phase)
Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2). The
design and main results of INTERACT2 have been described elsewhere.[10,11]. In brief,
INTERACT2 was an international, multicenter, open, blinded endpoint, randomized controlled trial [12]. A total of 2839 patients with CT-confirmed spontaneous ICH, elevated systolic BP (SBP, 150-220mmHg), and capacity to commence BP lowering treatment (<6h of
onset assessed by ‘time last seen normal’), were enrolled from 144 hospitals in 21 countries
between 7th October 2008 and 30th August 2012. Patients were excluded if they had a structural cerebral cause for the ICH, deep coma (defined as a score of 3–5 on the Glasgow coma
2 / 14
scale [GCS] [13], where scores range from 3 to 15, with lower scores indicating reduced levels
of consciousness), massive hematoma with a poor prognosis, or if early surgery to evacuate the
hematoma was planned. Eligible patients were randomly assigned to receive intensive (target
SBP <140mmHg within 1h) or guideline recommended (SBP <180mmHg) BP treatment. In
order to minimize assessor bias, the primary outcome of ‘death or major disability’ (as measured by the modified Rankin scale) at 90 days was evaluated by clinicians who were blind to
the randomized treatment. The date of the final patient follow up was 31 December 2012.
We obtained hourly ambient temperature data primarily from Weatherbank Inc (Edmond,
US) which directly sources weather observations from worldwide government agencies that
represent the official source of data in different countries. Data from the Australian Bureau of
Meteorology was also used. For the main analyses, we linked baseline data of 1997 individual
patients (70%) to hourly temperature data from monitoring stations less than 100km from the
patients’ hospital of enrolment.
Statistical Analyses
Baseline characteristics of the included patients were compared to those excluded in models
using chi-square or Wilcoxon rank sum tests. We applied a time-stratified, case-crossover analysis to the data with the preceding 24h period of the reported ICH onset time selected as the
case period for each ICH event [14–16]. Control periods of exposure were defined as the comparable 24h before the ICH in the other weeks of the same month and year. This method of
selecting control periods has been shown to effectively control for time invariant confounders
and seasonality, whilst also avoiding the problems of time trend and overlap bias associated
with other methods of referent selection [16,17]. Thus, each participant was represented with a
matched set of data for 1 case period and 3–4 control periods.
We assessed the risk of ICH in a distributed lag non-linear model (DLNM) which was originally developed to estimate the non-linear and delayed effects of temperature (or air pollution)
on mortality or morbidity [18,19]. We applied recent developments in the method that
extended DLNMs beyond time series data, and made it applicable in a case-crossover study
design [20]. The DLNM involves a bi-dimensional space of functions that describes simultaneously the shape of the relationship along both the space of the predictor and the lag dimension of its occurrence. We modeled the exposure-response function with a natural cubic spline
with internal knots placed at quartiles of ambient temperature and a reference temperature of
20°C (taken as the average optimal temperature of comfort for humans) [21], and the lagresponse function was modeled with a natural cubic spline with two equally spaced internal
knots in log-scale. A bi-dimensional plot was constructed to demonstrate the entire relationship between temperature and ICH risk whilst also taking into account the time sequence of
effect. Lag-response curves were plotted to describe the evolving temporal change in ICH risk
in a 24 h lag period after exposure to specific temperatures in comparison to a reference optimal temperature of 20°C. Furthermore, the effect of temperature was summarized in an overall
cumulative exposure-response figure which shows the net increased ICH risk over an entire lag
period of 24 h in association with temperature exposure, accounting for any harvesting or
lagged effects. Finally, our results were also presented as overall cumulative odds ratios (ORs)
and 95% confidence intervals (CI) that were computed by summation of the lag-specific risk
contributions for a given pattern of temperature exposures during the 24 hours lag period. The
statistical equation describing the DLNM model and derivation of the overall cumulative odds
ratio is outlined elsewhere [20].
In order to check the robustness of the study results, several sensitivity analyses were performed; by inclusion of all patients with known hourly temperature data within 200km of the
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Table 1. Patient characteristics.
Variable
Included patients (n = 1997)
Excluded patients (n = 832)
p value
Time from ICH onset to randomization, median (IQR), h:min
3:38 (2:45–4:40)
3:58 (3:00–4:40)
<0.001
Age, mean (SD), y
65 (13)
61 (12)
<0.001
Male
1252 (63)
528 (63)
0.70
Hypertension
1441 (72)
607 (73)
0.57
Previous ICH
150 (8)
79 (10)
0.07
Ischemic stroke
196 (10)
90 (11)
0.40
Diabetes mellitus
227 (11)
78 (9)
0.13
Medical history
Drug use
Antihypertensive therapy
170 (9)
107 (13)
<0.001
Antiplatelet therapy
225 (11)
40 (5)
<0.001
Warfarin anticoagulation
75 (4)
6 (1)
<0.001
SBP, mean (SD), mmHg
179 (17)
180 (17)
0.13
DBP, mean (SD), mmHg
100 (15)
104 (13)
<0.001
Clinical features
Heart rate, mean(SD), bpm
78 (14)
78 (14)
0.22
NIHSS score,a median (IQR)
10 (6–16)
11 (7–16)
0.31
GCS score,b median (IQR)
14 (13–15)
14 (12–15)
<0.001
Lobar
213 (11)
47 (7)
Deep
1569 (83)
601 (84)
Brainstem
52 (3)
28 (4)
Cerebellum
58 (3)
31 (4)
Baseline ICH volume, median (IQR), mL
10.6 (5.5–19.1)
11.8 (6.7–20.1)
0.01
Intensive BP treatment
989 (50)
410 (49)
0.91
ICH location
0.01
Data are n (%), mean (SD), or median (IQR).
Comparisons for continuous and categorical variables were made using Wilcoxon and chi-square tests respectively.
ICH indicates intracerebral hemorrhage; SBP
systolic blood pressure; DBP, diastolic blood pressure; NIHSS, National Institute of Health stroke scale; GCS, Glasgow coma scale; BP, blood pressure.
a
NIHSS can range from 0 (normal, no neurological deﬁcit) to 42 (coma with quadriplegia).
GCS scores can range from 3 (deep coma) to 15 (normal, alert)
b
doi:10.1371/journal.pone.0149040.t001
site of enrolment, which totalled 2346 (83%); and by extending the maximum lag length from
24 to 72 h. All analyses were performed using SAS 9.2 (SAS Institute Inc., Cary, NC) and R
project for statistical computing V.3.1.0 using the ‘dlnm’ and ‘survival’ packages.
Results
Table 1 shows the baseline demographic and clinical characteristics of patients with available
ambient temperature data (‘included patients’, n = 1997) and those without such data
(‘excluded patients’, n = 832). Those without this data were significantly younger, had less
prior use of antithrombotic therapy, higher diastolic BP, and more likely to have lobar ICH
and larger hematoma volumes. The weather parameters of the 79 cities included in analyses
are outlined in the S1 Table.
Fig 1 shows the bi-dimensional exposure-lag-response surface, depicting changes across
temperature and lags with a trend of higher ORs at low ambient temperatures and shorter time
lags. The lag-exposure plots in Fig 2 indicates an elevated risk of ICH in association with
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Fig 1. Bi-dimensional exposure-lag-response plot of intracerebral hemorrhage risk. The exposureresponse function was modeled with a natural cubic spline with internal knots placed at quartiles of ambient
temperature (and a reference temperature of 20°C), and the lag-response function was modeled with a
natural cubic spline with two equally spaced internal knots in log-scale.
doi:10.1371/journal.pone.0149040.g001
exposure to low ambient temperature (10°C) between lag 0 to lag 3 and that a harvesting
effect seems to exist at longer lags. The main results of our study are shown in Fig 3, which
reflects the relationship between low temperature exposure and ICH risk. A total number of
1568 (79%) ICH cases occurred below the optimal reference temperature. The overall cumulative ORs for ICH progressively increased from 1.37 (0.99–1.91) for 10°C, 1.92 (1.31–2.81) for
0°C, 3.13 (1.89–5.19) for -10°C, and 5.76 (2.30–14.42) for -20°C.
Fig 4 shows a temporal pattern to the occurrence of ICH, with peak frequencies in the early
morning (06:00–10:00) and evening (20:00–23:00), but no clear relationship with the level of
SBP among patients at the time of entry into the trial.
Results of sensitivity analyses including all patients with known hourly temperature data
within 200km of the site of enrolment and extending the maximum lag length from 24 to 72h
all produced similar results (S1–S3 Figs).
Discussion
To our knowledge, this is the first large-scale international study to have investigated the association between ambient temperature and ICH risk at an hourly resolution and to capture the
time sequence of the detrimental effect of low ambient temperature. Using distributed lag nonlinear model fitted to a case-crossover model involving 1997 well-characterized ICH patients,
we found a clear association of low ambient temperature with ICH occurrence within a few
hours of exposure.
5 / 14
Fig 2. Lag-exposure plots of intracerebral hemorrhage risk for specific temperatures. CI indicates confidence interval. Case (n) indicates the number
of ICH events in each temperature exposure category.
Several but not all studies have reported an association between low ambient temperature
and ICH [2–5,22–24]. This discrepancy may be due to the use of daily temperature parameters
that may not be truly representative of the temperature at the time of ICH onset. Furthermore,
previous studies involved subjects from single regions, some of which have relatively small variations in temperature throughout the year. Our study using hourly temperature data in a large
international study population corroborates the findings of a Taiwanese study with known
hourly temperature data at ICH onset which showed a trend of increased ICH occurrence
towards the lower temperature and is also consistent with prior investigations and clinical
observation of a peak ICH occurrence in the winter due in part to the trigger effect of low ambient temperature on the risk of ICH onset at particular times of the day [2–5,25]. Mechanisms
underlying the increased ICH risk in colder climate have not been resolved but exposure to low
temperatures has been shown to stress the sympathetic nervous system leading to acute
increases in heart rate, peripheral resistance, and thereby BP [26,27]. Although acute increases
in BP associated with exposure to low ambient temperature is the most plausible trigger of
ICH, we were unable to find any correlation between admission SBP level and ambient temperature, nor any differences in risks between those with and without a history of hypertension.
This could be because the admission systolic BP of participants may not be representative of
their BP level close to the time of ICH onset, or that ICH patients with non-elevated BP were
excluded from our study.
6 / 14
Previous studies have reported upon a temperature effect for up to 14 days for the occurrence of myocardial infarction [6,7]. However, our study results show no association of low
temperature beyond several hours prior to ICH onset and this finding is further supported by
sensitivity analysis with extended lag period of 72 h. The differences in these risk time periods
may be attributable to the distinctions in pathological mechanisms of onset for myocardial
infarction (being plaque rupture from atherothrombosis) and ICH (being mainly due to the
rupture of small deep perforating intracerebral vessels).
Key strengths of this study include the large sample of a wide range of patients with early
and rigorous standardised evaluations of clinical and imaging findings after acute ICH. Also
we were able to attain reliable hourly temperature weather data and link this information to the
baseline patient characteristics to conduct precise evaluations on the effects of low ambient
temperature. Our case-crossover model with control periods stratified by calendar month
inherently adjusted for potential confounders, such as slow time varying individual characteristics, time of the day, day of the week, and seasonality. Furthermore, we were also able to avoid
problems of time trend and overlap bias associated with other methods of control selection
[16,17].
Fig 3. Overall cumulative odds ratio plot of temperature effect.
7 / 14
Fig 4. Temporal pattern of intracerebral hemorrhage onset and baseline systolic blood pressure level in patients. ICH indicates intracerebral
hemorrhage; SBP, systolic blood pressure.
There are several limitations to our study. First, the study population is subject to varying
levels of selection bias that may limit the generalizability of the results. Being a clinical trial
population, patients with a poor prognosis due to massive hematoma or deep coma, and in
whom early surgery was planned, were excluded. Therefore, future studies on a general ICH
population are necessary to validate our findings. Another issue is that we were unable to
obtain (100km) hourly temperature data for 30% of participants (‘excluded patients’), of
which the majority were from second to third tier cities in China (Baotou, Xuzhou, Wenzhou
and Xining). Differences in the provision of healthcare and medical development, and diet and
lifestyles, may have resulted in significant differences in characteristics such as ‘time from
onset to randomization’ and use of medications (e.g. antihypertensives and antithrombotics)
and contribute to variability in severity of hospital presentation and prognosis, thus limiting
the generalizability of our findings. However, sensitivity analyses that included approximated
temperature of Baotou (83%) showed a slight increase in ICH risk in association with low temperature in comparison to the primary analyses. A further issue relates to the precision of the
exposure temperature data, as some of our weather data for the main analyses originated from
monitoring stations up to 100 kilometres away from participating hospitals. However, this may
likely have generated a non-differential misclassification that biased the result toward the null,
and therefore produced conservative estimates of the true risk. We were also unable to account
for potential confounding from individual changes in behaviour and cold protection. We may
have been able to partly mitigate this problem through use of the case-crossover design and
control selection strategy as the pattern of activity and clothing habits of individuals are likely
8 / 14
to remain consistent at across times of the day, days of the week, and within a one-month calendar period. It is also interesting to note that a Eurowinter group study reported no associations between indoor heating, clothing protection, and even sweating, with reductions in
cerebrovascular disease related mortality [28]. While we were unable to collect information on
other potential confounders, such as the patients’ emotional state that could have a bearing on
BP variability, the presence of viral infections, usage of sympathomimetics and of other
weather parameters or air pollution, these are also assumed to be constant in case-crossover
analysis. Finally, as the study was post-hoc, we cannot exclude the play of chance and reliably
establish a causal relationship between low ambient temperature and ICH occurrence.
In conclusion, the present findings based on 1997 patients from a large global study show
an increased risk of ICH within a few hours of exposure to very low ambient temperature. The
risk of ICH in high-risk subjects might be reduced by more stringent monitoring and management of BP levels during cold seasons, targeted personal advice and environmental heating
interventions, triggered by forecasts of very low temperature.
Supporting Information
S1 Fig. Overall cumulative odds ratio plot for temperature effects using approximated
weather data. CI indicates confidence interval.
(TIFF)
S2 Fig. Overall cumulative odds ratio plot for temperature effects with extended 72h lag
period. CI indicates confidence interval.
(TIFF)
S3 Fig. Lag-exposure plots of intracerebral hemorrhage for specific temperatures with
extended 72h lag period. CI indicates confidence interval.
(TIFF)
S1 Table. Weather characteristics of all included INTERACT2 cities.
(DOCX)
Acknowledgments
INTERACT2 Investigators
Executive Committee: C.S. Anderson (principal investigator), J. Chalmers (chair), H. Arima,
S. Davis, E. Heeley, Y. Huang, P. Lavados, B. Neal, M.W. Parsons, R. Lindley, L. Morgenstern,
T. Robinson, C. Stapf, C. Tzourio, J.G. Wang. National Leaders: China—Steering Committee:
Y. Huang (chair), S. Chen, X.Y. Chen, L. Cui, Z. Liu, C. Lu, J. Wang, S. Wu, E. Xu, Q. Yang, C.
Zhang, J. Zhang. Europe—Austria: R. Beer, E. Schmutzhard; Belgium: P. Redondo; Finland: M.
Kaste, L. Soinne, T. Tatlisumak; France: C. Stapf; Germany: K. Wartenberg; Italy: S. Ricci; The
Netherlands: K. Klijn; Portugal: E. Azevedo; Spain: A. Chamorro; Switzerland: M. Arnold, U.
Fischer; India: S. Kaul, J. Pandian, H. Boyini, S. Singh; North America–A.A. Rabinstein; South
America—Argentina–C. Estol; Brazil–G. Silva; Chile–P. Lavados, V.V. Olavarria; and United
Kingdom–T.G. Robinson. Data Safety and Monitoring Committee: R.J. Simes (chair), M.-G.
Bousser, G. Hankey, K. Jamrozik (deceased), S.C. Johnston, and S. Li. Project Office Operations Committee: E. Heeley (study director), C.S. Anderson, K. Bailey, J. Chalmers, T. Cheung,
C. Delcourt, S. Chintapatla, E. Ducasse, T. Erho, J. Hata, B. Holder, E. Knight, R. Lindley, M.
Leroux, T. Sassé, E. Odgers, R. Walsh, and Z. Wolfowicz. Endpoint Adjudication Committee:
C.S. Anderson, G. Chen, C. Delcourt, S. Fuentes, R. Lindley, B. Peng, H.-M. Schneble, and M.-
9 / 14
X. Wang. Statistical Analysis: H. Arima, L. Billot, S. Heritier, Q. Li, and M. Woodward. CT
Analyses: C. Delcourt (chair), S. Abimbola, S. Anderson, E. Chan, G. Cheng, P. Chmielnik, J.
Hata, S. Leighton, J.-Y. Liu, B. Rasmussen, A. Saxena, and S. Tripathy. Data Management and
Programming: M. Armenis, M.A. Baig, B. Naidu, G. Starzec, and S. Steley. Coordinating Centers: International (The George Institute for Global Health, Sydney, Australia)–C.S. Anderson,
E. Heeley, M. Leroux, C. Delcourt, T. Sassé, E. Knight, K. Bailey, T. Cheung, E. Odgers, E.
Ducasse, B. Holder, Z. Wolfowicz, R. Walsh, S. Chintapatla, T. Erho; Argentina, Buenos Aires
(STAT Research)–C. Estol, A. Moles, A. Ruiz, M. Zimmermann; Brazil, Fortaleza (Medicamenta MRS)–J. Marinho, S. Alves, R. Angelim, J. Araujo, L. Kawakami; Chile, Santiago (Clínica
Alemana, Universidad del Desarrollo)–P. Lavados, V.V. Olavarria, C. Bustos, F. Gonzalez, P.
Munoz Venturelli; China, Beijing (The George Institute China incorporating George Clinical,
and Peking University First Hospital)–Y. Huang, X. Chen, Y. Huang, R. Jia, N. Li, S. Qu, Y.
Shu, A. Song, J. Sun, J. Xiao, and Y. Zhao; China, Shanghai (The Centre for Epidemiological
Studies and Clinical Trials, The Shanghai Institute of Hypertension, Rui Jin Hospital, Shanghai
Jiaotong University School of Medicine)—J.G. Wang, Q. Huang; Europe, Paris (Unité de
Recherche Clinique, APHP—Hôpital Lariboisière)–C. Stapf, E. Vicaut, A. Chamam, M.-C.
Viaud, C. Dert, U. Fiedler, V. Jovis, S. Kabla, S. Marchand, A. Pena, V. Rochaud; India, Hyderabad (The George Institute India)–K. Mallikarjuna H. Boyini, N. Hasan; Norway, Oslo (Oslo
University Hospital)–E. Berge, E.C. Sandset, A.S. Forårsveen; United Kingdom (Department of
Cardiovascular Sciences, University of Leicester)–T. Robinson, D. Richardson, T. Kumar, S.
Lewin; United Kingdom (London, Imperial Clinical Trials Unit)—N. Poulter, J. Field, A.
Anjum, A. Wilson. Principal Investigators and Coordinators (according to country and center): Argentina—Clínica Instituto Medico Adrogue: H. Perelmuter, A.M. Agarie; Hospital Central de Mendoza: A.G. Barboza, L.A. Recchia, I.F. Miranda, S.G. Rauek, R.J. Duplessis;
Australia—Austin Hospital: H. Dewey, L. Walker, S. Petrolo; Box Hill: C. Bladin; Gosford Hospital: J. Sturm, D. Crimmins, D. Griffiths, A. Schutz, V. Zenteno; John Hunter Hospital: M.W.
Parsons, F. Miteff, N. Spratt, E. Kerr, C.R. Levi; Monash Medical Centre: T.G. Phan, H. Ma, L.
Sanders, C. Moran, K. Wong; Royal Brisbane and Women's Hospital: S. Read, R. Henderson,
A. Wong, R. Hull, G. Skinner; Royal Melbourne Hospital: S. Davis, P. Hand, B. Yan, H. Tu, B.
Campbell; Royal Prince Alfred Hospital): C.S. Anderson, C. Delcourt; Sir Charles Gairdner
Hospital: D.J. Blacker; Western Hospital: T. Wijeratne, M. Pathirage, M. Jasinararchchi, Z.
Matkovic, S. Celestino; Austria—Allgenmeines Krankenhaus Linz: F. Gruber, M.R. Vosko, E.
Diabl, S. Rathmaier; Innsbruck Medical University—Department of Neurology: R. Beer, E.
Schmutzhard, B. Pfausler, R. Helbok; Medical University of Graz, Department of Neurology: F.
Fazekas, R. Fischer, B. Poltrum, B. Zechner, U. Trummer; Belgium—Cliniques De L'Europe
(Europe Clinic): M.P. Rutgers; UCL St Luc: A. Peeters, A. Dusart, M.-C. Duray, C. Parmentier,
S. Ferrao-Santos; Universitair Ziekenhuis Brussel: R. Brouns, S. De Raedt, A. De Smedt, R.-J.
VanHooff, J. De Keyser; Brazil—Hospital das Clínicas de Porto Alegre: S.C.O. Martins, A.G. de
Almeida, R. Broudani, N.F. Titton; Hospital Quinta D'Or: G.R. de Freitas, F.M. Cardoso, L.M.
Giesel, N.A. Lima Junior; Hospital Santa Marcelina: A.C. Ferraz de Almeida, R.B. Gomes, T.S.
Borges dos Santos, E.M. Veloso Soares, O.L.A. Neto; Universidade Federal de São Paulo: G.S.
Silva, D.L. Gomes, F.A. de Carvalho, M. Miranda, A. Marques; Universidade Federal do
Paraná: V.F. Zétola, G. de Matia, M.C. Lange; Chile—Clinica Alemana de Santiago: J. Montes,
A. Reccius, P. Munoz Venturelli, V.V. Olavarria, A. Soto; Clínica Alemana de Temuco, Chile:
R. Rivas, C. Klapp; Clínica Dávila: S. Illanes, C. Aguilera, A. Castro; Complejo Asistencial Dr.
Víctor Ríos Ruiz: C. Figueroa, J. Benavides, P. Salamanca, M.C. Concha, J. Pajarito; Hospital
Naval Almirante Nef: P. Araya, F. Guerra; China—Baotou Central Hospital: Y. Li, G. Liu, B.
Wang, J. Zhang, Y. Chong; Beijing Shijitan Hospital: M. He, L. Wang, J. Liu; Beijing Tongren
Hospital: X. Zhang, C. Lai, H. Jiang, Q. Yang, S. Cui; Chang Ning District Central Hospital: Q.
10 / 14
Tao, Y. Zhang, S. Yao, M. Xu, Y. Zhang; Changsha Central Hospital: Z. Liu, H. Xiao, J. Hu, J.
Tang; Gongli Hospital, Pudong New Area, Shanghai: J. Sun, H. Ji, M. Jiang; Haidian Hospital,
Beijing: F. Yu, Y. Zhang, X. Yang, X. Guo; Hejian City People's Hospital: Y. Wang, L. Wu, Z.
Liu, Y. Gao, D. Sun; Hunan Province Brain Hospital: X. Huang, Y. Wang, L. Liu, Y. Li, P. Li;
Jiangsu Province Hospital of Traditional Chinese Medicine: Y. Jiang, H. Li, H. Lu; Nanjing
First Hospital: J. Zhou, C. Yuan; Navy General Hospital: X. Qi, F. Qiu, H. Qian, W. Wang, J.
Liu; Peking University First Hospital: Y. Huang, W. Sun, F. Li, R. Liu, Q. Peng; Peking University Shougang Hospital: Z. Ren, C. Fan, Y. Zhang, H. Wang, T. Wang; People's Hospital of Beijing Daxing District: F. Shi, C. Duan, S. Chen, J. Wang, Z. Chen; Pinggu County Hospital,
Beijing: X. Tan, Z. Zhao, Y. Gao, J. Chen, T. Han; Qinghai Province People's Hospital: S. Wu,
L. Zhang, L. Wang, Q. Hu, Q. Hou; Qinghai University Affiliated Hospital: X. Zhao, L. Wang,
G. Zeng, L. Ma, F. Wang; Ruijin Hospital Affiliated to Shanghai Jiaotong University School of
Medicine: S. Chen, L. Zeng, Z. Guo, Y. Fu, Y. Song; Second Hospital of Hebei Medical University: L. Tai, X. Liu, X. Su, Y. Yang, R. Dong; Shijiazhuang 260 Hospital: Y. Xu, S. Tian, S.
Cheng, L. Su, X. Xie; The Affiliated Hospital of Xuzhou Medical College: T. Xu, D. Geng, X.
Yan, H. Fan, N. Zhao; The Branch Hospital of the First People's Hospital: S. Wang, J. Yang;
The Chinese PLA No. 263 Hospital: J. Zhang, M. Yan, L. Li; The Fifth Affiliated Hospital Sun
Yat-Sen University: Z. Li, X. Xu, F. Wang; The First Affiliated Hospital of Baotou Medical College: L. Wu, X. Guo, Y. Lian, H. Sun, D. Liu; The First Affiliated Hospital of Fujian Medical
University: N. Wang, Q. Tang; The First Affiliated Hospital of Wenzhou Medical College: Z.
Han, L. Feng; The Fourth Hospital of Jilin University: Y. Cui, J. Tian, H. Chang, X. Sun, J.
Wang; The Second Affiliated Hospital Suzhou University: C. Liu, Z. Wen; The Second Affiliated Hospital of Guangzhou Medical College: E. Xu, Q. Lin; The Second Affiliated Hospital of
Wenzhou Medical College: X. Zhang, L. Sun, B. Hu, M. Zou, Q. Bao; The Second Hospital of
Qinghuangdao: X. Lin, L. Zhao, X. Tian, H. Wang, X. Wang; The Second Hospital of Tianjin
Medical University: X. Li, L. Hao, Y. Duan, R. Wang, Z. Wei; Third Hospital of Hebei Medical
University: J. Liu, S. Ren, H. Ren, Y. Wang, Y. Dong; Tianjin Medical University General Hospital: Y. Cheng, M. Zou, W. Liu, J. Han, C. Zhang; Tianjin Third Central Hospital: Z. Zhang, J.
Zhu, Y. Wang, Q. Li; Traditional Chinese Medicine Hospital, Zhangjiagang: J. Qian, Y. Sun, K.
Liu, F. Long; Wangcheng County People's Hospital of Hunan Province: X. Peng, Q. Zhang, Z.
Yuan, C. Wang, M. Huang; Wuxi People's Hospital: J. Zhang, F. Wang, P. He, Y. You, X.
Wang; Xiangya Hospital Central-South University: Q. Yang, H. Wang, J. Xia, L. Zhou, Y. Hou;
Xining First People's Hospital: Y. Wang, L. Liu, Y. Qi, L. Mei, R. Lu; Xuzhou Central Hospital:
G. Chen, L. Liu, L. Ping, W. Liu, S. Zhou; Yutian County Hospital, Hebei Province: J. Wang, L.
Wang, H. Li, S. Zhang, L. Wang; Zengcheng People's Hospital: R. Zou, J. Guo, M. Li, W. Wei;
Finland—Helsinki University Central Hospital: L. Soinne, S. Curtze, M. Saarela, D. Strbian, F.
Scheperjans; France—Centre Hospitalier de Saint Denis–Hôpital Delafontaine: T. De Broucker,
C. Henry, R. Cumurciuc, N. Ibos-Augé; Centre Hospitalier de Versailles André-Mignot: A.-C.
Zéghoudi, F. Pico; CH Calais: O. Dereeper, M.-C. Simian, C. Boisselier, A. Mahfoud; CHRU de
Brest: S. Timsit, F.M. Merrien; CHU de Nantes—Hôpital G&R Laënnec: B. Guillon, M. Sevin,
F. Herisson, C. Magne; Hôpital de Meaux: A. Ameri, C. Cret, S. Stefanizzi, F. Klapzcynski;
Hôpital Kremlin Bicêtre: C. Denier, M. Sarov-Riviere; Hôpital Lariboisière: C. Stapf, P. Reiner,
J. Mawet, D. Hervé, F. Buffon; Hôpital Ste-Anne: E. Touzé, V. Domigo, C. Lamy, D. Calvet, M.
Pasquini; Hôpital Tenon: S. Alamowitch, P. Favrole, I.-P. Muresan; Pitié Salpêtrière: S. Crozier,
C. Rosso, C. Pires, A. Leger, S. Deltour; Roger Salengro Lille: C Cordonnier, H. Henon, C.
Rossi; Service de Neurologie et Neurovasculaire, Groupe Hospitalier Paris Saint Joseph: M.
Zuber, M. Bruandet, R. Tamazyan, C. Join-Lambert; Germany—Charité-University Medicine
Berlin—Center for Stroke Research Berlin (CSB): E. Juettler, T. Krause, S. Maul, M. Endres, G.
J. Jungehulsing; Department of Neurology University of Heidelberg UMM Mannheim: M.
11 / 14
Hennerici, M. Griebe, T. Sauer, K. Knoll; Department of Neurology, University of Ulm: R.
Huber, K. Knauer, C. Knauer, S. Raubold; Dresden University of Technology, University Hospital, Department of Neurology: H. Schneider, H. Hentschel, C. Lautenschläger, E. Schimmel,
I. Dzialowski; Goethe University Hospital Frankfurt: C. Foerch, M. Lorenz, O. Singer, I.M. R.
Meyer dos Santos; Klinikum Frankfurt (Oder): A. Hartmann, A. Hamann, A. Schacht, B.
Schrader, A. Teíchmann; Martin Luther University: K.E. Wartenberg, T.J. Mueller; University
Hospital Düsseldorf: S. Jander, M. Gliem, C. Boettcher; University Medical Center Hamburg–
Eppendorf: M. Rosenkranz, C. Beck, D. Otto, G. Thomalla, B. Cheng; Hong Kong—Prince of
Wales Hospital, Chinese University of Hong Kong: K.S. Wong, T.W. Leung, Y.O.Y. Soo; India
—Apollo Hospitals: S. Prabhakar, S.R. Kesavarapu, P.K. Gajjela, R.R. Chenna; Baby Memorial
Hospital: K. Ummer, M. Basheer, A. Andipet; CARE Hospital, Nampally: M.K.M. Jagarlapudi,
A.U.R. Mohammed, V.G. Pawar, S.S.K. Eranki; Christian Medical College & Hospital: J. Pandian, Y. Singh, N. Akhtar; GNRC Hospitals: N.C. Borah, M. Ghose, N. Choudhury; Jehangir
Clinical Development Centre Pvt Ltd: N.R. Ichaporia, J. Shendge, S. Khese; Lalitha Super Specialities Hospital: V. Pamidimukkala, P. Inbamuthaiah, S.R. Nuthakki, N.M.R. Tagallamudi, A.
K. Gutti; Postgraduate Institute of Medical Education & Research: D. Khurana, P. Kesavarapu,
V. Jogi, A. Garg, D. Samanta; St. John's Medical College & Hospital (1): G.R.K. Sarma, R.
Nadig, T. Mathew, M.A. Anandan; Italy—Central follow up for Italy: E. Caterbi; Nuovo Ospedale Civile, AUSL Modena: A. Zini, M. Cavazzuti, F. Casoni, R. Pentore, F. Falzone; Ospedale
di Branca: S. Ricci, T. Mazzoli, L.M. Greco, C. Menichetti, F. Coppola; Ospedale di Città di Castello: S. Cenciarelli, E. Gallinella, A. Mattioni, R. Condurso, I. Sicilia; San Giovanni Battista: M.
Zampolini, F. Corea, M. Barbi, C. Proietti; Sapienza University Unità di Trattamento Neurovascolare: D. Toni, A. Pieroni, A. Anzini, A. Falcou, M. Demichele; The Netherlands—University Medical Center Utrecht (2): C.J.M. Klijn; Norway—Sørlandet Sykehus HF Kristiansand: A.
Tveiten, E.T. Thortveit, S. Pettersen; Sykehuset Innlandet HF Lillehammer: N. Holand, B. Hitland; University Hospital North Norway: S.H. Johnsen, A. Eltoft; Pakistan–Aga Khan University: M. Wasay, A. Kamal, A. Iqrar, L. Ali, D. Begum; Portugal—Centro Hospitalar Sao Joao: G.
Gama, E. Azevedo, L. Fonseca, G. Moreira; Centro Hospitalar Vila Nova de Gaia: L.M. Veloso,
D. Pinheiro, L. Paredes, C. Rozeira, T. Gregorio; Spain—Complejo Hospitalario Universitario
de Albacete: T. Segura Martin, O. Ayo, J. Garcia-Garcia, I. Feria Vilar, I. Gómez Fernández;
Hospital Clinico de Barcelona: A. Chamorro, S. Amaro, X. Urra, V. Obach, A. Cervera; Hospital Universitari de Girona, Dr Josep Trueta: Y. Silva, J. Serena, M. Castellanos, M. Terceno, C.
Van Eendenburg; Switzerland—University of Bern, Inselspital: U. Fischer, M. Arnold, A.
Weck, O. Findling, R. Lüdi; United Kingdom—Addenbrookes Hospital: E.A. Warburton, D.
Day, N. Butler, E. Bumanlag; Bristol Royal Infirmary: S. Caine, A. Steele, M. Osborn, E. Dodd,
P. Murphy; County Durham & Darlington NHS Foundation Trust: B. Esisi, E. Brown, R. Hayman, V. K.V. Baliga, M. Minphone; John Radcliffe Hospital: J. Kennedy, I. Reckless, G. Pope,
R. Teal, K. Michael; King's College Hospital: D. Manawadu, L. Kalra, R. Lewis, B. Mistry, E.
Cattermole; Leeds General Infirmary: A. Hassan, L. Mandizvidza, J. Bamford, H. Brooks, C.
Bedford; Musgrove Park Hospital: R. Whiting, P. Baines, M. Hussain, M. Harvey; New Cross
Hospital: K. Fotherby, S. McBride, P. Bourke, D. Morgan, K. Jennings-Preece; Northumbria
Healthcare–Wansbeck and North Tyneside General Hospitals: C. Price, S. Huntley, V.E. Riddell, G. Storey, R.L. Lakey; Nottingham University Hospital: G. Subramanian; Royal Bournemouth Hospital: D. Jenkinson, J. Kwan, O. David, D. Tiwari; Royal Devon and Exeter Hospital:
M. James, S. Keenan, H. Eastwood; Royal United Hospital Bath NHS Trust: L. Shaw, P. Kaye,
D. Button, B. Madigan, D. Williamson; Royal Victoria Infirmary Hospital NHS Foundation
Trust: A. Dixit, J. Davis, M.O. Hossain, G.A. Ford; Salford Royal NHS Foundation Trust: A.
Parry-Jones, V. O'Loughlin, R. Jarapa, Z. Naing; St George's Healthcare NHS Trust: C. Lovelock, J. O'Reilly, U. Khan; St. Thomas Hospital: A. Bhalla, A. Rudd, J. Birns; University College
12 / 14
London Hospitals NHS Foundation Trust: D.J. Werring, R. Law, R. Perry, I. Jones, R. Erande;
University Hospital of North Staffordshire (2): C. Roffe, I. Natarajan, N. Ahmad, K. Finney, J.
Lucas; University Hospitals of Leicester NHS Trust: A. Mistri, D. Eveson, R. Marsh, V. Haunton, T. Robinson; USA—Mayo Clinic: A.A. Rabinstein, J.E. Fugate, S.W. Lepore.
Author Contributions
Conceived and designed the experiments: DZ HA EH CSA. Analyzed the data: DZ HA AG SL.
Contributed reagents/materials/analysis tools: HA EH CD YH JW CS TR PL JC CSA. Wrote
the paper: DZ HA SS. Critical appraisal of the study: HA SS AG EH CD SL YH JW CS TR PL
JC CSA. Supervision of the study: CSA.
References
1.
Krishnamurthi RV, Feigin VL, Forouzanfar MH, Mensah GA, Connor M, Bennett DA, et al. Global and
regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the
Global Burden of Disease Study 2010. Lancet Glob Health. 2013; 1(5): e259–81. doi: 10.1016/S2214109X(13)70089-5 PMID: 25104492
2.
Rothwell PM, Wroe SJ, Slattery J, Warlow CP. Is stroke incidence related to season or temperature?
The Oxfordshire Community Stroke Project. Lancet. 1996; 347(9006): 934–6. PMID: 8598757
3.
Gomes J, Damasceno A, Carrilho C, Lobo V, Lopes H, Madede T, et al. Triggering of stroke by ambient
temperature variation: a case-crossover study in Maputo, Mozambique. Clin Neurol Neurosur. 2015;
129: 72–7.
4.
Ohwaki K, Yano E, Murakami H, Nagashima H, Nakagomi T. Meteorological factors and the onset of
hypertensive intracerebral hemorrhage. Int J Biometeorol. 2004; 49(2): 86–90. PMID: 15257452
5.
Passero S, Reale F, Ciacci G, Zei E. Differing temporal patterns of onset in subgroups of patients with
intracerebral hemorrhage. Stroke. 2000; 31(7): 1538–44. PMID: 10884450
6.
Bhaskaran K, Hajat S, Haines A, Herrett E, Wilkinson P, Smeeth L. Short term effects of temperature
on risk of myocardial infarction in England and Wales: time series regression analysis of the Myocardial
Ischaemia National Audit Project (MINAP) registry. BMJ. 2010; 341: c3823. doi: 10.1136/bmj.c3823
PMID: 20699305
7.
Schwartz J, Samet JM, Patz JA. Hospital admissions for heart disease: the effects of temperature and
humidity. Epidemiology. 2004; 15(6): 755–61. PMID: 15475726
8.
Fischer U, Cooney MT, Bull LM, Silver LE, Chalmers J, Anderson CS, et al. Acute post-stroke blood
pressure relative to premorbid levels in intracerebral haemorrhage versus major ischaemic stroke: a
population-based study. Lancet Neurol. 2014; 13(4): 374–84. doi: 10.1016/S1474-4422(14)70031-6
PMID: 24582530
9.
Wei JW, Arima H, Huang Y, Wang JG, Yang Q, Liu Z, et al. Variation in the frequency of intracerebral
haemorrhage and ischaemic stroke in China: a national, multicentre, hospital register study. Cerebrovasc Dis. 2010; 29(4): 321–7. doi: 10.1159/000278927 PMID: 20130397
10.
Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. Rapid blood-pressure lowering in
patients with acute intracerebral hemorrhage. N Engl J Med. 2013; 368(25): 2355–65. doi: 10.1056/
NEJMoa1214609 PMID: 23713578
11.
Delcourt C, Huang Y, Wang J, Heeley E, Lindley R, Stapf C, et al. The second (main) phase of an open,
randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction
in acute cerebral haemorrhage trial (INTERACT2). Int J Stroke. 2010; 5(2): 110–6. doi: 10.1111/j.17474949.2010.00415.x PMID: 20446945
12.
Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (PROBE) study. A
novel design for intervention trials. Prospective randomized open blinded end-point. Blood Press.
1992; 1(2):113–9. PMID: 1366259
13.
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet.
1974; 2(7872): 81–4. PMID: 4136544
14.
Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute
events. Am J Epidemiol. 1991; 133(2): 144–53. PMID: 1985444
15.
Whitaker HJ, Hocine MN, Farrington CP. On case-crossover methods for environmental time series
data. Environmetrics. 2007; 18(2): 157–171.
13 / 14
16.
Janes H, Sheppard L, Lumley T. Case-crossover analyses of air pollution exposure data: referent
selection strategies and their implications for bias. Epidemiology. 2005; 16(6): 717–26. PMID:
16222160
17.
Mittleman MA. Optimal referent selection strategies in case-crossover studies: a settled issue. Epidemiology. 2005; 16(6): 715–6. PMID: 16222159
18.
Armstrong B. Models for the relationship between ambient temperature and daily mortality. Epidemiology. 2006; 17(6): 624–31. PMID: 17028505
19.
Gasparrini A, Armstrong B, Kenward MG. Distributed lag non-linear models. Stat Med. 2010; 29(21):
2224–34. doi: 10.1002/sim.3940 PMID: 20812303
20.
Gasparrini A. Modeling exposure-lag-response associations with distributed lag non-linear models.
Stat Med. 2014; 33(5): 881–99. doi: 10.1002/sim.5963 PMID: 24027094
21.
Gasparrini A, Guo Y, Hashizume M, Lavigne E, Zanobetti A, Schwartz J, et al. Mortality risk attributable
to high and low ambient temperature: a multicountry observational study. Lancet. 2015; 386(9991):
369–75. doi: 10.1016/S0140-6736(14)62114-0 PMID: 26003380
22.
Sobel E, Zhang ZX, Alter M, Lai SM, Davanipour Z, Friday G, et al. Stroke in the Lehigh Valley: seasonal variation in incidence rates. Stroke. 1987; 18(1): 38–42. PMID: 3810768
23.
Dawson J, Weir C, Wright F, Bryden C, Aslanyan S, Lees K, et al. Associations between meteorological
variables and acute stroke hospital admissions in the West of Scotland. Acta Neurol Scand. 2008; 117
(2): 85–89. doi: 10.1111/j.1600-0404.2007.00916.x PMID: 18184342
24.
Jeong TS, Park CW, Yoo CJ, Kim EY, Kim YB, Kim WK. Association between the daily temperature
range and occurrence of spontaneous intracerebral hemorrhage. J Cerebrovasc Endovasc Neurosurg.
2013; 15(3): 152–157. doi: 10.7461/jcen.2013.15.3.152 PMID: 24167793
25.
Fang CW, Ma MC, Lin HJ, Chen CH. Ambient temperature and spontaneous intracerebral haemorrhage: a cross-sectional analysis in Tainan, Taiwan. BMJ Open. 2012; 2(3).
26.
Aubiniere-Robb L, Jeemon P, Hastie CE, Patel RK, McCallum L, Morrison D, et al. Blood pressure
response to patterns of weather fluctuations and effect on mortality. Hypertension. 2013; 62(1): 190–6.
doi: 10.1161/HYPERTENSIONAHA.111.00686 PMID: 23648702
27.
Alperovitch A, Lacombe JM, Hanon O, Dartigues JF, Ritchie K, Ducimetiere P, et al. Relationship
between blood pressure and outdoor temperature in a large sample of elderly individuals: the ThreeCity study. Arch Intern Med. 2009; 169(1): 75–80. doi: 10.1001/archinternmed.2008.512 PMID:
19139327
28.
Keatinge WR, Donaldson GC, Bucher K, Cordioli E, Dardanoni L, Jendritzky G, et al. Cold exposure
and winter mortality from ischaemic heart disease, cerebrovascular disease, respiratory disease, and
all causes in warm and cold regions of Europe. Lancet. 1997; 349(9062): 1341–1346. PMID: 9149695
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